Orphan drug development in muscular dystrophy: update on two large clinical trials of dystrophin rescue therapies.
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Duchenne muscular dystrophy is a relatively common 'rare disorder,' with an incidence of about 1/5,000 males worldwide. The responsible gene and deficient protein (dystrophin) were identified in 1987, an early success of human molecular genetics and emerging genome projects. A rational approach to therapeutics is to replace dystrophin in patient muscle, thus addressing the primary biochemical defect. Fast forward 25 years, and two phase 2b/3 trials have been carried out with agents designed to induce de novo dystrophin production in DMD patient's muscle; ataluren (stop codon read through) with 174 patients, and drisapersen (exon skipping) with 186 patients. Both used a six minute walk test as the primary outcome measure. Neither drisapersen nor high dose ataluren showed any significant improvement in this outcome, whereas low dose ataluren is reported to show some possible improvement. Experience with ataluren and drisapersen has been disappointing and this is a good time to ask: What can we learn from these programs and how can this inform further drug development in DMD? At the times these two trials were started, there was a lack of existing data and infrastructure regarding both clinical and biochemical outcome measures. The recent publications of more extensive natural history data in multiple DMD cohorts, and ongoing efforts to define reliable and sensitive dystrophin assays are important. If the drisapersen and ataluren programs were instead begun today, new progress in biochemical and clinical endpoints may have triggered a re-design, with better de-risking in phase 2 studies prior to resource-intensive phase 3 trials. (+info)
Drug development for exceptionally rare metabolic diseases: challenging but not impossible.
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Reconciling uncertainty of costs and outcomes with the need for access to orphan medicinal products: a comparative study of managed entry agreements across seven European countries.
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Legal instruments supporting the development of orphan medicinal products in the European Union.
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Securing the freedoms of the Internal Market by the European Union entails an obligation to implement such mechanisms so that medicinal products placed on the market could be, on the one hand, widely available to the citizens of Member States and, on the other, so that medicinal products could be both safe and effective. The first aspect involves acting towards the improvement of public health and the prevention of human diseases and troubles, while the second--removing the sources of danger to human health. From this perspective, we need to highlight the problem of a deficit in the development, and thus a deficit in the availability of medicinal products authorized for marketing, which are intended for use in rare diseases. This paper aims to analyze the European Union pharmaceutical law in order to establish whether, and if yes--how the EU legal regulations support the development and availability of orphan medicinal products on the Internal Market. (+info)